Title
Comparison of short- and long-acting GLP-1 receptor agonists on glucose excursion, insulin/glucagon secretions and gastric emptying


Background
Several glucagon-like peptide-1 receptor (GLP-1R) agonists are available to manage type 2 diabetes. GLP-1R agonists can be classified as either short-acting or long-acting agents depending on pharmacokinetic differences. Short-acting agents (e.g., exenatide and lixisenatide) strongly lower postprandial, but not fasting, blood glucose levels, whereas long acting agents (e.g., liraglutide, dulaglutide and exenatide LAR) ameliorates both fasting and postprandial glucose levels. Several studies suggest that different effects of long-acting and short-acting agents on glycemic control comes from distinct mode of actions of the two agents: Long-acting might ameliorate glucose levels by ameliorating insulin and glucagon secretions; and short-acting by inhibiting gastric emptying. However, these models has not been fully tested until now. 

Aim
The aim of this study is to clarify the differences between lixisenatide (short-acting GLP-1RA T1/2 : 2.8hr) , liraglutide (long-acting GLP-1RA T1/2 : 11-15hr) and dulaglutide (long-acting GLP-1RA T1/2 : 108hr) on postprandial glucose excursions, insulin- and glucagon-secretion and gastric-emptying in Japanese individuals with type 2 diabetes.

Method
Non-Randomized, parallel study were performed. Meal tolerance tests with C13 breath tests were performed before, 2weeks after and 12weeks after administration of each GLP-1 RA. Blood sampling (Plasma Glucose, Glucagon, Insulin) and breath sampling (C13 / C12 ratio of exhaled air) were measured.
Carbon-thirteen breathe test is measurements of CO2 consisting of C13 to estimate gastric emptying rate. Non-invasive stable carbon-thirteen isotope in the acetate in the test meal is emptied from the stomach and transported to the liver via the portal vein, where it is oxidized to CO2 consisting of C13, end-tidal breath samples are collected and carbon-thirteen content is measured using isotope ratio mass spectrometry. Results are reported as mean ± SEM. Data were evaluated using student’s or paired t-test. p<0.05 was considered significant.

Result
The characteristics of patients at baseline was as follows : Lixisenatide (N=6; age 47.7±6.7; duration 5.5±5.4 years;Δglucagon stimulation test (GST) 2.8±0.9 ng/ml) , Liraglutide (N=6; age 49.0±11.4; duration 8.2±9.2 years ΔGST 3.1±0.5 ng/ml) , Dulaglutide (N=4; age 53.8±7.2; duration 8.5±7.0 years ΔGST 3.2±1.3 ng/ml). All subjects were naïve Japanese type 2 diabetes patients.Both Lixisenatide and Liraglutide significantly reduced HbA1c and body weight at 12 weeks after administration (HbA1c(%): Lixisenatide, 7.7±1.0 to 6.3±0.4; Liraglutide 9.0±0.8 to 6.6±1.1; BW(kg): Lixisenatide 92.3±26.4 to 89.3±27.1; Liraglutide 81.9±12.1 to 75.9±9.0). On the other hand, Dulaglutide group also significantly reduced HbA1c, but did not reduce body weight at 12 weeks after administration (HbA1c(%) Dulaglutide, 8.3±1.3 to 6.6±0.4; BW(kg) 78.6±23.5 to 77.2±21.4).Lixisenatide ameliorated postprandial glucose excursion, whereas Liraglutide and Dulaglutide ameliorated fasting and postprandial glucose excursion. Lixisenatide decreased postprandial insulin response. Liraglutide and Dulaglutide increased relative insulin response. In pre-and post-prandial glucagon levels, no significant difference was detected in Lixisenatide, Liraglutide and Dulaglutide groups. Lixisenatide significantly slowed gastric emptying at 12 weeks after administration(T1/2(min): Lixisenatide, 24.1±3.8 to 62.0±36.7). In Liraglutide and Dulaglutide group, we did not detect any changes in gastric emptying (T1/2(min): Liraglutide, 33.5±15.5 to 29.1±9.2; Dulaglutide, 25.5±7.9 to 31.3±10.6).

Discussion
These results support the notion that long-acting agents improve glycemic control through enhanced insulin secretion and that short-acting agents do so through delayed gastric emptying.

Comparison of short- and long-acting GLP-1RA on glucose excursion, insulin/glucagon secretions and gastric emptying